In stable stroke, reinstating vascular flow is imperative for restoring nutrient supply in the brain. To repair vascular damage after prolonged ischemia at least two sequential steps are needed. The first step is angiogenic sprouting of endothelial cells (ECs); this process entails the initial proliferation of endothelial cells and remodeling of the surrounding extracellular matrix. VEGF-mediated prolifdation of ECs and matrix metalloproteinases are among the major components of angiogenic sprouting. The second step is vessel stabilization; a process that relies on recruitment of vascular smooth muscle cells to encase the young vessels. Monocytes and pericytes are also involved in vessel stabilization, producing the appropriate arteriogenic factors and extracellular matrix proteins. In the absence of vessel stabilization by smooth muscle cells and pericytes, regression of nascent vasculature can occur.
Marrow stromal cells (MSCs, also known as mesenchymal stem cells)) have been shown to promote revascularization after cerebral artery occlusion and traumatic brain in jury. Omori et al. (2008) Brain Res. 1236:30-38; Onda et al. (2008) J. Cereb. Blood Flow Metab. 28:329-340; Pavlichenko et al. (2008) Brain Res. 1233:203-213; Xiong et al.(2009) Brain Res. 1263:183-191. SB623 cells are a derivative of marrow stromal cells, obtained by transfecting marrow stromal cells with a vector containing sequences encoding a Notch intracellular domain (NICD). See, for example, U.S. Pat. No. 7,682,825 and Dezawa et al. (2004) J. Clin. Investig. 13:1701-1710. SB623 cells elicit functional improvement in experimental stroke models. See, for example, U.S. Pat. No. 8,092,792 and Yasuhara et al. (2009) Stem Cells and Development 18:1501-1514. Although the secretome of SB623 cells is comparable to that of the parental MSCs; different levels of specific trophic factors have been observed to be secreted by MSCs, as compared to SB623 cells. See, for example, Tate et al. (2010) Cell Transplantation 19:973-984; U.S. Patent Application Publication No. 2010/0266554. Moreover, many of the factors whose expression levels differ between MSCs and SB623 cells have been reported to be involved in vascular regeneration.
Because stroke is a leading cause of adult disability in the United States, and is the second leading cause of death worldwide, there remains a need for treatments to restore blood supply to, and promote reperfusion of, regions of stroke-induced ischemic damage in the brain.